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1.
Artículo en Inglés | MEDLINE | ID: mdl-33822512

RESUMEN

The purpose of this study was to investigate the anti-inflammatory, antiproliferatiive, and proapoptotic molecular mechanisms of mangiferin (MGN) against mammary carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA). Mammary cancer in rats was induced by single-dose subcutaneous injection of 0.5 ml DMBA (80 mg/kg in sesame oil) in the mammary gland. Increased tumor incidence and volume and other tumorigenic properties were observed. Further, we observed in these rats reduced antioxidant enzyme activity and elevated thiobarbituric acid reactive substance (TBARS) levels in plasma and tissues. DMBA-induced rats shows enhanced expression of the inflammatory markers NF-κBp65, COX-2, and iNOS and proliferation of PCNA and Cyclin D1, and overexpression of the antiapoptotic marker Bcl-2. Mangiferin (100 mg/kg body weight), administered orally once per day, significantly enhanced (p < 0.05) antioxidant levels and reduced TBARS levels. Moreover, MGN inhibited NF-κBp65 nucleus transcriptional activation, thereby suppressing inflammation and cell proliferation, and it increased proapoptotic proteins. Apoptosis was confirmed by TUNEL assay. In summary, MGN suppressed DMBA-induced mammary carcinogenesis through enhanced antioxidant levels, NF-κB inhibition, and positive regulation of apoptotic signals.


Asunto(s)
Antiinflamatorios/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , FN-kappa B/antagonistas & inhibidores , Xantonas/uso terapéutico , 9,10-Dimetil-1,2-benzantraceno , Animales , Antiinflamatorios/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinógenos , Proliferación Celular/efectos de los fármacos , Femenino , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , FN-kappa B/metabolismo , Ratas Sprague-Dawley , Xantonas/farmacología
2.
Anticancer Res ; 41(4): 1841-1847, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813389

RESUMEN

BACKGROUND/AIM: Homeobox A9 (HOXA9), a transcription factor regulating haematopoiesis and leukaemia cell proliferation, is suggested as a driver of acute myeloid leukaemia (AML). The aim of this study was to examine the effects of a synthetic HOXA9 inhibitor DB818 on AML cells in vitro. MATERIALS AND METHODS: AML cell lines OCI/AML3, MV4-11, and THP-1 with gene mutations up-regulating HOXA9 expression were treated with DB818 and analysed for cell proliferation and gene expression. The effects of HOXA9 knockdown were also evaluated. RESULTS: In the three AML cell lines, DB818 suppressed growth, induced apoptosis, and down-regulated the expression of HOXA9 transcriptional target genes: MYB proto-oncogene, transcription factor (MYB), MYC proto-oncogene, bHLH transcription factor (MYC), and BCL2 apoptosis regulator (BCL2), while up-regulating that of Fos proto-oncogene, AP-1 transcription factor subunit (FOS). HOXA9 knockdown showed similar effects, except for MYC expression, which differed between DB818-treated and HOXA9-deficient OCI/AML3 cells, suggesting an off-target effect of DB818. CONCLUSION: DB818 has potential as a novel molecular targeted drug for treating AML associated with HOXA9 overexpression.


Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Proteínas de Homeodominio/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Regulación Leucémica de la Expresión Génica , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Transducción de Señal , Células THP-1
3.
Anticancer Res ; 41(4): 1859-1870, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813391

RESUMEN

BACKGROUND/AIM: Demethoxycurcumin (DMC), one of the derivatives of curcumin, has been shown to induce apoptotic cell death in many human cancer cell lines. However, there is no available information on whether DMC inhibits metastatic activity in human glioblastoma cancer cells in vitro. MATERIALS AND METHODS: DMC at 1.0-3.0 µM significantly decreased the proliferation of GBM 8401 cells; thus, we used 2.0 µM for further investigation regarding anti-metastatic activity in human glioblastoma GBM 8401 cells. RESULTS: The internalized amount of DMC has reached the highest level in GBM 8401 cells after 3 h treatment. Wound healing assay was used to determine cell mobility and results indicated that DMC suppressed cell movement of GBM 8401 cells. The transwell chamber assays were used for measuring cell migration and invasion and results indicated that DMC suppressed cell migration and invasion in GBM 8401 cells. Gelatin zymography assay was used to examine gelatinolytic activity (MMP-2) in conditioned media of GBM 8401 cells treated by DMC and results demonstrated that DMC significantly reduced MMP-2 activity. Western blotting showed that DMC reduced the levels of p-EGFR(Tyr1068), GRB2, Sos1, p-Raf, MEK, p-ERK1/2, PI3K, p-Akt/PKBα(Thr308), p-PDK1, NF-κB, TIMP-1, MMP-9, MMP-2, GSK3α/ß, ß-catenin, N-cadherin, and vimentin, but it elevated Ras and E-cadherin at 24 h treatment. CONCLUSION: DMC inhibited cancer cell migration and invasion through inhibition of PI3K/Akt and NF-κB signaling pathways in GBM 8401 cells. We suggest that DMC may be used as a novel anti-metastasis agent for the treatment of human glioblastoma cancer in the future.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Diarilheptanoides/farmacología , Glioblastoma/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Glioblastoma/enzimología , Glioblastoma/patología , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , FN-kappa B/metabolismo , Invasividad Neoplásica , Transducción de Señal , beta Catenina/metabolismo
4.
Anticancer Res ; 41(4): 1883-1893, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813393

RESUMEN

BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is a highly prevalent disease and treatment is limited. Therefore, development of new therapeutic agents is urgent. The aim of this study was to investigate the in vitro and in vivo anti-cancer effects of Nardostachys jatamansi root extract (NJRE) against HCC and underlying mechanisms involved in such effects. MATERIALS AND METHODS: Effects of NJRE on viability of HCC cell lines were determined by MTT analysis and annexin/PI apoptosis assays. Expression levels of proteins in MAPK and STAT3 pathways and caspase-3 and PARP after treatment with NJRE in HCC cell lines were determined by western blotting. In a syngeneic model using mouse HCC cells Hepa1-6, inhibition of tumor formation after oral administration of NJRE was determined and expression levels of phospho-ERK and phospho-STAT3 in liver tissues were analyzed by immunohistochemical staining. RESULTS: NJRE reduced the activation of STAT3 by inhibiting the expression of ERK and finally attenuated the proliferation of HCC. CONCLUSION: NJRE has anti-cancer effects against HCC. It has potential to be used in the treatment of human HCC.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Nardostachys , Raíces de Plantas , Factor de Transcripción STAT3/metabolismo , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Masculino , Ratones Endogámicos C57BL , Nardostachys/química , Fosforilación , Raíces de Plantas/química , Transducción de Señal , Carga Tumoral/efectos de los fármacos
5.
Nat Commun ; 12(1): 1536, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750776

RESUMEN

Hyperactivation of the MAPK signaling pathway motivates the clinical use of MAPK inhibitors for BRAF-mutant melanomas. Heterogeneity in differentiation state due to epigenetic plasticity, however, results in cell-to-cell variability in the state of MAPK dependency, diminishing the efficacy of MAPK inhibitors. To identify key regulators of such variability, we screen 276 epigenetic-modifying compounds, individually or combined with MAPK inhibitors, across genetically diverse and isogenic populations of melanoma cells. Following single-cell analysis and multivariate modeling, we identify three classes of epigenetic inhibitors that target distinct epigenetic states associated with either one of the lysine-specific histone demethylases Kdm1a or Kdm4b, or BET bromodomain proteins. While melanocytes remain insensitive, the anti-tumor efficacy of each inhibitor is predicted based on melanoma cells' differentiation state and MAPK activity. Our systems pharmacology approach highlights a path toward identifying actionable epigenetic factors that extend the BRAF oncogene addiction paradigm on the basis of tumor cell differentiation state.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Epigenómica/métodos , Melanoma/metabolismo , Dependencia del Oncogén , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Femenino , Histona Demetilasas/metabolismo , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Melanocitos/metabolismo , Melanoma/genética , Ratones , Ratones Desnudos , Mutación , Dependencia del Oncogén/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Nat Commun ; 12(1): 1521, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750801

RESUMEN

Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.


Asunto(s)
Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Masculino , Ratones , Ratones SCID , Organoides , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Nat Commun ; 12(1): 1812, 2021 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-33753739

RESUMEN

Human hexokinase 2 is an essential regulator of glycolysis that couples metabolic and proliferative activities in cancer cells. The binding of hexokinase 2 to the outer membrane of mitochondria is critical for its oncogenic activity. However, the regulation of hexokinase 2 binding to mitochondria remains unclear. Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K492. SUMO-specific protease SENP1 mediates the de-SUMOylation of hexokinase 2. SUMO-defective hexokinase 2 preferably binds to mitochondria and enhances both glucose consumption and lactate production and decreases mitochondrial respiration in parallel. This metabolic reprogramming supports prostate cancer cell proliferation and protects cells from chemotherapy-induced cell apoptosis. Moreover, we demonstrate an inverse relationship between SENP1-hexokinase 2 axis and chemotherapy response in prostate cancer samples. Our data provide evidence for a previously uncovered posttranslational modification of hexokinase 2 in cancer cells, suggesting a potentially actionable strategy for preventing chemotherapy resistance in prostate cancer.


Asunto(s)
Carcinogénesis/metabolismo , Hexoquinasa/metabolismo , Mitocondrias/metabolismo , Neoplasias de la Próstata/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismo , Docetaxel/farmacología , Hexoquinasa/genética , Humanos , Masculino , Ratones , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Unión Proteica , Sumoilación , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
8.
Molecules ; 26(5)2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33668096

RESUMEN

Aizoaceae is a large succulent family characterized by many psychoactive species. Aizoon canariense L., a wild neglected plant traditionally used in gastrointestinal ailments, has been the subject of a limited number of phytochemical and biological studies. Therefore, herein, we investigated the in vitro cytotoxic, antimicrobial, and anticholinesteraseactivity of the aerial parts of A. canariense L. and analyzed the phytochemical compositions of the lipoidal and alkaloidal fractions. Petroleum ether extract showed the presence of behenic and tricosylic acid, while an in-depth investigation of the alkaloidal fraction revealed the identification of new adenine based alkaloids (1-5), which were isolated and identified for the first time from Aizoon canariense L. Their structures were elucidated based on extensive spectroscopic analyses. The alkaloidal extract showed a powerful cytotoxic effect (IC50 14-28 µg/mL), with the best effect against colon carcinoma, followed by liver and breast carcinomas. The alkaloidal extract also had a potent effect against Candida albicans and Escherichia coli, with minimum inhibitory concentrations (MIC) values of 312.5 and 625 µg/mL. The in vitro anticholinesterase activity was potent, with IC50 < 200 ng/mL for the tested extracts compared with 27.29 ± 0.49 ng/mL for tacrine.


Asunto(s)
Aizoaceae/química , Alcaloides/farmacología , Antibacterianos/farmacología , Antifúngicos/farmacología , Antineoplásicos Fitogénicos/farmacología , Inhibidores de la Colinesterasa/farmacología , Extractos Vegetales/farmacología , Acetilcolinesterasa/metabolismo , Alcaloides/química , Alcaloides/aislamiento & purificación , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Candida albicans/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Escherichia coli/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Relación Estructura-Actividad
9.
Molecules ; 26(5)2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33668169

RESUMEN

A series of fifteen silver (I) quinoline complexes Q1-Q15 have been synthesized and studied for their biological activities. Q1-Q15 were synthesized from the reactions of quinolinyl Schiff base derivatives L1-L5 (obtained by condensing 2-quinolinecarboxaldehyde with various aniline derivatives) with AgNO3, AgClO4 and AgCF3SO3. Q1-Q15 were characterized by various spectroscopic techniques and the structures of [Ag(L1)2]NO3Q1, [Ag(L1)2]ClO4Q6, [Ag(L2)2]ClO4Q7, [Ag(L2)2]CF3SO3Q12 and [Ag(L4)2]CF3SO3Q14 were unequivocally determined by single crystal X-ray diffraction analysis. In vitro antimicrobial tests against Gram-positive and Gram-negative bacteria revealed the influence of structure and anion on the complexes' moderate to excellent antibacterial activity. In vitro antioxidant activities of the complexes showed their good radical scavenging activity in ferric reducing antioxidant power (FRAP). Complexes with the fluorine substituent or the thiophene or benzothiazole moieties are more potent with IC50 between 0.95 and 2.22 mg/mL than the standard used, ascorbic acid (2.68 mg/mL). The compounds showed a strong binding affinity with calf thymus-DNA via an intercalation mode and protein through a static quenching mechanism. Cytotoxicity activity was examined against three carcinoma cell lines (HELA, MDA-MB231, and SHSY5Y). [Ag(L2)2]ClO4Q7 with a benzothiazole moiety and [Ag(L4)2]ClO4Q9 with a methyl substituent had excellent cytotoxicity against HELA cells.


Asunto(s)
Antibacterianos/farmacología , Antineoplásicos/farmacología , Antioxidantes/farmacología , Complejos de Coordinación/farmacología , ADN/química , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antioxidantes/síntesis química , Antioxidantes/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Férricos/antagonistas & inhibidores , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Oxidación-Reducción , Quinolinas/química , Quinolinas/farmacología , Bases de Schiff/química , Bases de Schiff/farmacología , Plata/química , Plata/farmacología
10.
Molecules ; 26(5)2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33668176

RESUMEN

Colorectal cancer is a common cancer worldwide and reduced expression of the DNA repair endonuclease XPF (xeroderma pigmentosum complementation group F) is associated with colorectal cancer. Bacopa monnieri extracts were previously found to exhibit chemical-genetic synthetic lethal effects in a Saccharomyces cerevisiae model of colorectal cancer lacking Rad1p, a structural and functional homologue of human XPF. However, the mechanisms for B. monnieri extracts to limit proliferation and promote an apoptosis-like event in RAD1 deleted yeast was not elucidated. Our current analysis has revealed that B. monnieri extracts have the capacity to promote mutations in rad1∆ cells. In addition, the effects of B. monnieri extracts on rad1∆ yeast is linked to disruption of the vacuole, similar to the mammalian lysosome. The absence of RAD1 in yeast sensitizes cells to the effects of vacuole disruption and the release of proteases. The combined effect of increased DNA mutations and release of vacuolar contents appears to induce an apoptosis-like event that is dependent on the meta-caspase Yca1p. The toxicity of B. monnieri extracts is linked to sterol content, suggesting saponins may be involved in limiting the proliferation of yeast cells. Analysis of major constituents from B. monnieri identified a chemical-genetic interaction between bacopasaponin C and rad1∆ yeast. Bacopasaponin C may have potential as a drug candidate or serve as a model for the development of analogs for the treatment of colorectal cancer.


Asunto(s)
Bacopa/química , Enzimas Reparadoras del ADN/metabolismo , Endonucleasas/metabolismo , Glicósidos/farmacología , Extractos Vegetales/farmacología , Proteínas de Saccharomyces cerevisiae/metabolismo , Triterpenos/farmacología , Vacuolas/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Enzimas Reparadoras del ADN/deficiencia , Enzimas Reparadoras del ADN/genética , Endonucleasas/deficiencia , Endonucleasas/genética , Glicósidos/química , Extractos Vegetales/química , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Triterpenos/química , Vacuolas/metabolismo
11.
Molecules ; 26(4)2021 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-33670007

RESUMEN

A novel series of 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives were synthesized and evaluated against different tumor cell lines. Experiments in vitro showed that these derivatives could inhibit the proliferation of two kinds of human cancer cell lines (HepG2, HCT116) at low micromolar concentrations and the most potent analog 5q possessed broad-spectrum antiproliferative activity. Experiments in vivo demonstrated that 5q could effectively prolong the longevity of colon carcinoma-burdened mice and slow down the progression of cancer cells by suppression of angiogenesis and the induction of apoptosis and necrosis.


Asunto(s)
Antineoplásicos/farmacología , Ácidos Picolínicos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Ácidos Picolínicos/síntesis química , Ácidos Picolínicos/química , Células Tumorales Cultivadas
12.
Nat Commun ; 12(1): 1670, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33723267

RESUMEN

Effective healing of skin wounds is essential for our survival. Although skin has strong regenerative potential, dysfunctional and disfiguring scars can result from aberrant wound repair. Skin scarring involves excessive deposition and misalignment of ECM (extracellular matrix), increased cellularity, and chronic inflammation. Transforming growth factor-ß (TGFß) signaling exerts pleiotropic effects on wound healing by regulating cell proliferation, migration, ECM production, and the immune response. Although blocking TGFß signaling can reduce tissue fibrosis and scarring, systemic inhibition of TGFß can lead to significant side effects and inhibit wound re-epithelization. In this study, we develop a wound dressing material based on an integrated photo-crosslinking strategy and a microcapsule platform with pulsatile release of TGF-ß inhibitor to achieve spatiotemporal specificity for skin wounds. The material enhances skin wound closure while effectively suppressing scar formation in murine skin wounds and large animal preclinical models. Our study presents a strategy for scarless wound repair.


Asunto(s)
Cicatriz/terapia , Hidrogeles/farmacología , Iminas/química , Iminas/efectos de la radiación , Cicatrización de Heridas/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , Cicatriz/patología , Modelos Animales de Enfermedad , Matriz Extracelular/efectos de los fármacos , Femenino , Fibroblastos , Masculino , Ratones , Conejos , Transducción de Señal , Piel/patología , Sus scrofa , Factor de Crecimiento Transformador beta/efectos de los fármacos
13.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652632

RESUMEN

The use of bioresorbable fracture fixation plates made of aliphatic polyesters have good potential due to good biocompatibility, reduced risk of stress-shielding, and eliminated need for plate removal. However, polyesters are ductile, and their handling properties are limited. We suggested an alternative, PLAMA (PolyLActide functionalized with diMethAcrylate), for the use as the matrix phase for the novel concept of the in situ curable bioresorbable load-bearing composite plate to reduce the limitations of conventional polyesters. The purpose was to obtain a preliminary understanding of the chemical and physical properties and the biological safety of PLAMA from the prospective of the novel concept. Modifications with different molecular masses (PLAMA-500 and PLAMA-1000) were synthesized. The efficiency of curing was assessed by the degree of convergence (DC). The mechanical properties were obtained by tensile test and thermomechanical analysis. The bioresorbability was investigated by immersion in simulated body fluid. The biocompatibility was studied in cell morphology and viability tests. PLAMA-500 showed better DC and mechanical properties, and slower bioresorbability than PLAMA-1000. Both did not prevent proliferation and normal morphological development of cells. We concluded that PLAMA-500 has potential for the use as the matrix material for bioresorbable load-bearing composite fracture fixation plates.


Asunto(s)
Fijación de Fractura/métodos , Fracturas Óseas/terapia , Lactosa/análogos & derivados , Poliésteres/farmacología , Ácidos Polimetacrílicos/farmacología , Implantes Absorbibles/efectos adversos , Placas Óseas/efectos adversos , Proliferación Celular/efectos de los fármacos , Humanos , Lactosa/química , Lactosa/farmacología , Ensayo de Materiales , Poliésteres/química , Ácidos Polimetacrílicos/química , Estrés Mecánico , Resistencia a la Tracción , Soporte de Peso
14.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652694

RESUMEN

Colorectal cancer (CRC) is the third most common type of cancer worldwide and a leading cause of cancer death. According to the Malaysian National Cancer Registry Report 2012-2016, colorectal cancer was the second most common cancer in Malaysia after breast cancer. Recent treatments for colon cancer cases have caused side effects and recurrence in patients. One of the alternative ways to fight cancer is by using natural products. Curcumin is a compound of the rhizomes of Curcuma longa that possesses a broad range of pharmacological activities. Curcumin has been studied for decades but due to its low bioavailability, its usage as a therapeutic agent has been compromised. This has led to the development of a chemically synthesized curcuminoid analogue, (2E,6E)-2,6-bis(2,3-dimethoxybenzylidine) cyclohexanone (DMCH), to overcome the drawbacks. This study aims to examine the potential of DMCH for cytotoxicity, apoptosis induction, and activation of apoptosis-related proteins on the colon cancer cell lines HT29 and SW620. The cytotoxic activity of DMCH was evaluated using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) cell viability assay on both of the cell lines, HT29 and SW620. To determine the mode of cell death, an acridine orange/propidium iodide (AO/PI) assay was conducted, followed by Annexin V/FITC, cell cycle analysis, and JC-1 assay using a flow cytometer. A proteome profiler angiogenesis assay was conducted to determine the protein expression. The inhibitory concentration (IC50) of DMCH in SW620 and HT29 was 7.50 ± 1.19 and 9.80 ± 0.55 µg/mL, respectively. The treated cells displayed morphological features characteristic of apoptosis. The flow cytometry analysis confirmed that DMCH induced apoptosis as shown by an increase in the sub-G0/G1 population and an increase in the early apoptosis and late apoptosis populations compared with untreated cells. A higher number of apoptotic cells were observed on treated SW620 cells as compared to HT29 cells. Human apoptosis proteome profiler analysis revealed upregulation of Bax and Bad proteins and downregulation of Livin proteins in both the HT29 and SW620 cell lines. Collectively, DMCH induced cell death via apoptosis, and the effect was more pronounced on SW620 metastatic colon cancer cells, suggesting its potential effects as an antimetastatic agent targeting colon cancer cells.


Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Curcumina/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/patología , Curcuma/química , Curcumina/análogos & derivados , Curcumina/química , Diarilheptanoides/química , Diarilheptanoides/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HT29 , Humanos , Extractos Vegetales/química , Extractos Vegetales/farmacología
15.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652665

RESUMEN

The aim of the study was to investigate combined effects of flavonoids (apigenin, baicalein, chrysin, quercetin, and scutellarin) and methyldopa on the expression of selected proinflammatory and vascular factors in vitro for prediction of their action in pregnancy-induced hypertension. The research was conducted on a trophoblast-derived human choriocarcinoma cell line and a primary human umbilical vein endothelial cell line. Cytotoxicity of compounds in selected concentrations (20, 40, and 100 µmol) was measured using the MTT test and the concentration of 40 µmol was selected for further analysis. Subsequently, their effects with methyldopa on the expression of selected markers responsible for inflammation (TNF-α; IL-1ß; IL-6) and vascular effects (hypoxia-inducible factor 1α-HIF-1α; placental growth factor-PIGF; transforming growth factor ß-TGF-ß; vascular endothelial growth factor-VEGF) at the mRNA and protein levels were assessed. It was found that every combined administration of a flavonoid and methyldopa in these cells induced a down-regulating effect on all tested factors, except PIGF, especially at the mRNA expression level. As hypertension generally raises TNF-α, IL-1ß, IL-6, HIF-1α, TGF-ß, and VEGF mRNA expression and/or protein levels, the results obtained in the studied model may provide a positive prognostic factor for such activity in vivo.


Asunto(s)
Flavonoides/farmacología , Inflamación/tratamiento farmacológico , Metildopa/farmacología , Enfermedades Vasculares/tratamiento farmacológico , Línea Celular , Proliferación Celular/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Técnicas In Vitro , Inflamación/genética , Inflamación/patología , Placenta/efectos de los fármacos , Placenta/patología , Factor de Crecimiento Placentario/genética , Embarazo , Trofoblastos/efectos de los fármacos , Enfermedades Vasculares/genética , Enfermedades Vasculares/patología
16.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652854

RESUMEN

(2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) is a synthetic curcumin analogue, which has been reported to possess anti-tumor, anti-metastatic, and anti-invasion properties on estrogen receptor (ER) negative breast cancer cells in vitro and in vivo. However, the cytotoxic effects of BHMC on ER positive breast cancer cells were not widely reported. This study was aimed to investigate the cytotoxic potential of BHMC on MCF-7 cells using cell viability, cell cycle, and apoptotic assays. Besides, microarray and quantitative polymerase chain reaction (qPCR) were performed to identify the list of miRNAs and genes, which could be dysregulated following BHMC treatment. The current study discovered that BHMC exhibits selective cytotoxic effects on ER positive MCF-7 cells as compared to ER negative MDA-MB-231 cells and normal breast cells, MCF-10A. BHMC was shown to promote G2/M cell cycle arrest and apoptosis in MCF-7 cells. Microarray and qPCR analysis demonstrated that BHMC treatment would upregulate several miRNAs like miR-3195 and miR-30a-3p and downregulate miRNAs such as miR-6813-5p and miR-6132 in MCF-7 cells. Besides, BHMC administration was also found to downregulate few tumor-promoting genes like VEGF and SNAIL in MCF-7. In conclusion, BHMC induced apoptosis in the MCF-7 cells by altering the expressions of apoptotic-regulating miRNAs and associated genes.


Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , MicroARNs/genética , Antineoplásicos/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Curcumina/análogos & derivados , Curcumina/farmacología , Ciclohexanonas/farmacología , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7
17.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652957

RESUMEN

Multidrug resistance (MDR) remains a major problem in cancer therapy and is characterized by the overexpression of p-glycoprotein (P-gp) efflux pump, upregulation of anti-apoptotic proteins or downregulation of pro-apoptotic proteins. In this study, an Apolipoprotein A1 (ApoA1)-modified cationic liposome containing a synthetic cationic lipid and cholesterol was developed for the delivery of a small-molecule chemotherapeutic drug, doxorubicin (Dox) to treat MDR tumor. The liposome-modified by ApoA1 was found to promote drug uptake and elicit better therapeutic effects than free Dox and liposome in MCF-7/ADR cells. Further, loading Dox into the present ApoA1-liposome systems enabled a burst release at the tumor location, resulting in enhanced anti-tumor effects and reduced off-target effects. More importantly, ApoA1-lip/Dox caused fewer adverse effects on cardiac function and other organs in 4T1 subcutaneous xenograft models. These features indicate that the designed liposomes represent a promising strategy for the reversal of MDR in cancer treatment.


Asunto(s)
Apolipoproteína A-I/química , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/análogos & derivados , Apolipoproteína A-I/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Células MCF-7 , Polietilenglicoles/química , Polietilenglicoles/farmacología
18.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652969

RESUMEN

Cytotoxic flavonoids of Murraya tetramera were investigated in this study. A novel flavonoid and twelve known flavonoids, including seven flavones (1-7), three flavanones (8-10), and three chalcones (11-13) were isolated from the leaves and twigs of Murraya tetramera. Chemical structures were elucidated by NMR combined with MS spectral analysis, and the new compound (6) was confirmed as 3',5'-dihydroxy-5,6,7,4'-tetramethoxyflavone. Furthermore, all the isolated flavonoids were evaluated for their cytotoxicities against murine melanoma cells (B16), and human breast cancer cells (MDA-MB-231) by CCK-8 assay. Among them, compounds 7, 13, and 5 exhibited potent cytotoxic activities against B16 cell lines (IC50 = 3.87, 7.00 and 8.66 µg/mL, respectively). Compounds 5, 13, and 12 displayed potent cytotoxicities against MDA-MB-231 cell lines (IC50 = 3.80, 5.95 and 7.89 µg/mL, respectively). According to the correlation of the structure and activity analysis, 5-hydroxyl and 8-methoxyl substituents of the flavone, 8-methoxyl substituent of the flavanone, and 3',5'-methoxyl substituents of the chalcone could be critical factors of the high cytotoxicity. The results indicated that the active flavonoids have potential to be developed as leading compounds for treating cancers.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Proliferación Celular/efectos de los fármacos , Flavonoides/farmacología , Murraya/química , Animales , Antineoplásicos Fitogénicos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Chalconas/química , Chalconas/farmacología , Femenino , Flavonoides/química , Humanos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Ratones , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/farmacología , Hojas de la Planta/química
19.
Gene ; 782: 145542, 2021 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-33675953

RESUMEN

Squamous cell carcinoma (SCC) is a relatively common cancer with a low survival rate, poor prognosis and no effective treatment strategy. The use of cell-free conditioned media derived from mesenchymal stem cells (CM-MSCs) has shown promising results in treating various diseases. This study aimed to evaluate the effects of CM-MSCs on proliferation and apoptosis of CAL-27 and FaDu SCC cell lines. CM derived from human bone marrow and human amniotic membrane MSCs (BM-MSCs and AM-MSCs) was used in this investigation. MTT assay demonstrated that CM-BMMSC decreased the viability of CAL-27 and FaDu cell lines, 24, 48, and 72 h after treatment. Quantitative real-time PCR indicated that mRNA expression of PCNA as a proliferative marker, and BCL-2 as an anti-apoptotic protein, decreased in both cell lines treated with CM-BMMSC. Based on the flow cytometry results, the number of positive proliferative Ki67 cells and apoptotic Annexin-V cells decreased and increased in both cell lines treated with CM-BMMSC, respectively. However, CM-AMMSC treatment had both pro-and anti-neoplastic effects in our samples and showed considerable differences between the two cell lines. Taken together, our findings demonstrated that CM-BMMSC and, to a lesser degree, CM-AMMSC decrease cell viability and proliferation and increase cell apoptosis in SCC cell lines in a time-dependent manner. However, further studies are needed, especially to evaluate the anti-tumor potential of CM-BMMSC in vivo.


Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Células Madre Mesenquimatosas/metabolismo , Amnios/metabolismo , Células de la Médula Ósea , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Citometría de Flujo , Humanos , Neoplasias Hepáticas
20.
Nat Commun ; 12(1): 1912, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33771989

RESUMEN

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.


Asunto(s)
Neoplasias Encefálicas/genética , Glioblastoma/genética , Macrófagos/metabolismo , Microglía/metabolismo , Selectina-P/genética , Animales , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Células Cultivadas , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Células HEK293 , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones SCID , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Selectina-P/antagonistas & inhibidores , Selectina-P/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética
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